Breast cancer is the second leading cause of cancer-related death among women in the USA. Tobacco, a substance that contains human carcinogens, may contribute to the risk for breast cancer development in women. Large cohort epidemiological studies that were performed in the USA and Japan indicate that the risk for breast cancer is associated with both active and passive smoking. Cigarette smoke is a complex mixture of over 4,000 chemical constituents. On average, roughly 1.0 mg (range of 0.3-2.0 mg) of nicotine is absorbed systemically while smoking a cigarette, and studies performed using 14C-nicotine have shown that 80-90% of the inhaled nicotine is absorbed by the body. Nicotine concentrations in the plasma can reach levels of approximately 15 ng/ml immediately after smoking and even higher levels in the saliva and gastric juice (>1300 and >800 ng/ml, respectively). Previous studies using a soft agar transforming assay and a xenografted nude mouse animal model have shown that non-cancerous human breast epithelial (MCF-10A) cells are transformed by either a cigarette smoke condensate or the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In vivo studies have demonstrated that nicotine promotes the growth of solid tumors, which suggests that it might contribute to the progression of cell proliferation, invasion, and angiogenesis in tumors. Such results imply that nicotinic alteration of normal breast epithelial cells may also contribute to breast cancer tumorigenesis.
Among all body tissues, human neuronal tissues have been reported to exhibit the most abundant expression of nicotinic acetylcholine receptor (nAChR) subunits. These receptors are composed of either heteropentamers that comprise a combination of a (α1-α6) and b (β2-β4) subunits or homopentamers consisting of α7-α10 subunits that are symmetrically arranged around a central ion pore. The physiological ligand of nAChRs is acetylcholine; however, some tobacco components, including nicotine and its active metabolites, such as the nitrosamines N′-nitrosonornicotine and NNK, are high-affinity agonists of nAChRs. Recent studies have shown that nAChRs can accelerate cell proliferation, tumor invasion, and angiogenesis in addition to conferring resistance against apoptosis.
Most mammary carcinomas contain estrogen receptors (ER), which are important factors for diagnosis and prognosis of breast cancer, and for determining therapeutic choices (Osborne, 1998, Breast Cancer Res. Treat., 51, 227). Estrogens are direct mitogens for hormone-responsive human breast cancer cells, where they promote cell cycle progression and induce the transcriptional activation of “immediate early” and cyclin genes. The relationships between breast cancer formation, estrogen receptor (ER) (which mediates both hormone-induced gene transcription and anti-estrogen action against breast cancer), and ER ligands (such as estrogen, E2) have been discussed in a recent article (Chlebowski, R. T., Kuller, L. H., Prentice, R. L., Stefanick, M. L., Manson, J. E., Gass, M., Aragaki, A. K., Ockene, J. K., Lane, D. S., Sarto, G. E., et al. 2009. Breast cancer after use of estrogen plus progestin in postmenopausal women. N Engl J Med 360:573-587). E2, a group of steroid hormones, act primarily by regulating gene expression after binding to the ER, a nuclear ligand-activated transcription factor. The binding of an agonist (E2) induces a conformational change in the ER that enables it to homodimerize. This dimer is then translocated to the nucleus where it enhances gene transcription. ER activity may modulate the rate of transcription initiation by interacting with the basal transcriptional machinery and by changing the chromatin arrangement at the promoters of its target genes via the recruitment of a variety of coactivators. This ER/coactivator complex activates DNA transcription by stimulating E2 responsive elements (Brzozowski, A. M., Pike, A. C., Dauter, Z., Hubbard, R. E., Bonn, T., Engstrom, O., Ohman, L., Greene, G. L., Gustafsson, J. A., and Carlquist, M. 1997. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389:753-758). Additional target molecules that are involved in ER-mediated signaling pathways in breast cancer formation, however, remain to be identified.
Smoking and hormones are two important etiological factors involved in breast cancer formation (Daniell, H. W. 1980. Estrogen receptors, breast cancer, and smoking. N Engl J Med 302:1478). A recent study demonstrated that α9-nAChR expression plays a decisive role in smoking-induced breast cancer formation (Lee, C. H., Huang, C. S., Chen, C. S., Tu, S. H., Wang, Y. J., Chang, Y. J., Tam, K. W., Wei, P. L., Cheng, T. C., Chu, J. S., et al. 2010. Overexpression and activation of the alpha9-nicotinic receptor during tumorigenesis in human breast epithelial cells. J Natl Cancer Inst 102:1322-1335).
Therefore, there is a need to screen compounds that inhibit the α9-nAChR overexpression so as to treat and prevent nicotine-derived-compound-induced breast cancer.